Research Interests

Our laboratory investigates the pathogenesis of infection with Mycobacterium tuberculosis (Mtb) through a multidisciplinary approach that includes bacterial genetics, lipid biochemistry, and immunology. Tuberculosis remains a major cause of mortality worldwide and new antimicrobials that would shorten TBchemotherapy are badly needed. The unique cell envelope of Mtb is the target of multiple currently available antimycobacterial agents and has been suspected to be important for virulence. We are investigating the role of the Mtb cell envelope in pathogenesis through the characterization of bacterial mutants deficient in the synthesis of defined cell envelope compounds. Through this approach, we have delineated the crucial role of mycolic acid cyclopropane residues in the interaction of Mtb with the murine host. Mycolic acids are very long chain branched fatty acids that are only synthesized by mycobacteria. Of all mycobacteria, only pathogenic species modify their mycolic acids with cyclopropane residues through the action of a family of mycolic acid methyltransferase genes. We have found that perturbation of the cyclopropane content of the Mtb cell envelope through geneticdeletion of individual cyclopropane synthetase genes alters the symbiotic behavior of Mtb in mouse models of bacterial persistence. These cyclopropane synthetase mutants invoke distinct inflammatoryhistopathology, suggesting a role for individual cyclopropyl residues on mycolic acids in modulating the host immune response. These studies suggest that the exquisite chemical diversity of the Mtb cell envelope is an elaborate system of hydrophobic effector molecules that mediate host-pathogen interactions.

Our future work will focus on understanding the mechanisms by which the fine chemical structure of the Mtb cell envelope mediates host-pathogen interactions. These studies may identify novel targets for antimycobacterial drug development that would target persisting bacilli. In addition, understanding the host receptors that recognize these microbial products will lead to fundamental insights into the distinctive immunopathology of M. tuberculosis infection and into immune recognition of nonprotein microbial effector molecules.

acid (A-sid)

A chemical that gives off hydrogen ions in water and forms salts by combining with certain metals. Acids have a sour taste and turn certain dyes red. Some acids made by the body, such as gastric acid, can help organs work the way they should. An example of an acid is hydrochloric acid. Acidity is measured on a scale called the pH scale. On this scale, a value of 7 is neutral, and a pH value of less than 7 to 0 shows increasing acidity.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

analysis (uh-NA-lih-sis)

A process in which anything complex is separated into simple or less complex parts.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

apoptosis (A-pop-TOH-sis)

A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

ATP

A substance present in all living cells that provides energy for many metabolic processes and is involved in making RNA. ATP made in the laboratory is being studied in patients with advanced solid tumors to see if it can decrease weight loss and improve muscle strength. Also called adenosine triphosphate.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cancer (KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cell (sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

chemical (KEH-mih-kul)

A substance made up of elements, such as hydrogen or sodium.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

chemotherapy (KEE-moh-THAYR-uh-pee)

Treatment with drugs that kill cancer cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

deletion

Absence of a segment of DNA; may be as small as a single base or as large as a whole chromosome.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

DNA

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

domain

A specific physical region or amino acid sequence in a protein which is associated with a particular function or corresponding segment of DNA.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug (drug)

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug resistance (... reh-ZIH-stunts)

The failure of cancer cells, viruses, or bacteria to respond to a drug used to kill or weaken them. The cells, viruses, or bacteria may be resistant to the drug at the beginning of treatment, or may become resistant after being exposed to the drug.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

gene (jeen)

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetic (jeh-NEH-tik)

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetics (jeh-NEH-tix)

The study of genes and heredity. Heredity is the passing of genetic information and traits (such as eye color and an increased chance of getting a certain disease) from parents to offspring.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

histopathology (HIS-toh-puh-THAH-loh-jee)

The study of diseased cells and tissues using a microscope.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

hydrolysis (hy-DRAH-lih-sis)

A chemical reaction that uses water to break down a compound.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

immune response (ih-MYOON reh-SPONTS)

The activity of the immune system against foreign substances (antigens).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

immunology (IH-myoo-NAH-loh-jee)

The study of the body's immune system.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

in vivo (in VEE-voh)

In the body. The opposite of in vitro (outside the body or in the laboratory).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

infection (in-FEK-shun)

Invasion and multiplication of germs in the body. Infections can occur in any part of the body and can spread throughout the body. The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on where the infection occurs. When the body’s natural defense system is strong, it can often fight the germs and prevent infection. Some cancer treatments can weaken the natural defense system.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

inflammatory (in-FLA-muh-TOR-ee)

Having to do with inflammation (redness, swelling, pain, and a feeling of heat that helps protect tissues affected by injury or disease).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

interferon (in-ter-FEER-on)

A biological response modifier (a substance that can improve the body's natural response to infections and other diseases). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. The body normally produces these substances. They are also made in the laboratory to treat cancer and other diseases.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

L

A measure of volume for a liquid, using the metric system. One L is equal to 1,000 cubic centimeters (cc), 1,000 milliliters (mm), or 1.0567 quarts (qt). Also called liter.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

lipid (LIH-pid)

Fat.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

M

In chemistry, M is the amount of a substance that has 6.023 x 10(23) atoms or molecules of that substance. Also called mole (chemical).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

marker (MAR-ker)

A diagnostic indication that disease may develop.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

medicine (MEH-dih-sin)

Refers to the practices and procedures used for the prevention, treatment, or relief of symptoms of a diseases or abnormal conditions. This term may also refer to a legal drug used for the same purpose.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

membrane (MEM-brayn)

A very thin layer of tissue that covers a surface.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

mortality (mor-TA-lih-tee)

The state of being mortal (destined to die). Mortality also refers to the death rate, or the number of deaths in a certain group of people in a certain period of time. Mortality may be reported for people who have a certain disease, live in one area of the country, or who are of a certain gender, age, or ethnic group.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

multidisciplinary (MUL-tee-DIH-sih-plih-NAYR-ee)

In medicine, a term used to describe a treatment planning approach or team that includes a number of doctors and other health care professionals who are experts in different specialties (disciplines). In cancer treatment, the primary disciplines are medical oncology (treatment with drugs), surgical oncology (treatment with surgery), and radiation oncology (treatment with radiation).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

perturbation (PER-ter-BAY-shun)

A disruption or disturbance.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

response (reh-SPONTS)

In medicine, an improvement related to treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

T cell (... sel)

A type of immune cell that can attack foreign cells, cancer cells, and cells infected with a virus. T cells can also help control immune responses. A T cell is a type of white blood cell. Also called T lymphocyte and thymocyte.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

TB

A disease caused by a specific type of bacteria that spreads from one person to another through the air. TB can affect many parts of the body, but most often affects the lungs. A person may not have symptoms of TB for years, but they may appear when the patient becomes ill with a serious condition like diabetes, AIDS, or cancer. TB can usually be treated and cured with antibiotics. Also called tuberculosis.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

transcription (tran-SKRIP-shun)

In biology, the process by which a cell makes an RNA copy of a sequence of DNA that is a gene.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tuberculosis (too-BER-kyoo-LOH-sis)

A disease caused by a specific type of bacteria that spreads from one person to another through the air. Tuberculosis can affect many parts of the body, but most often affects the lungs. A person may not have symptoms of tuberculosis for years, but they may appear when the patient becomes ill with a serious condition like diabetes, AIDS, or cancer. Tuberculosis can usually be treated and cured with antibiotics. Also called TB.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

virulence (VEER-uh-lents)

The ability of a microorganism to cause damage to its host.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

will (wil)

A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)